The structural basis for tight control of PP2A methylation and function by LCMT-1.
The structural basis for tight control of PP2A methylation and function by LCMT-1.
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DOI：
10.1016/j.molcel.2010.12.030
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发表时间：
2011-02-04
期刊：
影响因子：
16
通讯作者：
Xing Y
中科院分区：
文献类型：
--
作者：
Stanevich V;Jiang L;Satyshur KA;Li Y;Jeffrey PD;Li Z;Menden P;Semmelhack MF;Xing Y
蛋白磷酸酶2A （PP2A）全酶的正确形成对所有真核细胞的适应度至关重要。PP2A催化亚基的羧基甲基化在调节全酶组装中起关键作用；甲基化是由pp2a特异性甲基转移酶LCMT-1催化的，LCMT-1是细胞存活所需的酶。我们测定了人LCMT-1的分离晶体结构和与辅因子模拟物稳定的PP2A复合物。结构表明，LCMT-1活性位点口袋识别PP2A的羧基端，有趣的是，PP2A活性位点与LCMT-1有广泛的接触。我们证明了PP2A活性位点的激活会刺激甲基化，这表明了一种将活化的PP2A有效转化为底物特异性全酶的机制，从而最大限度地减少了不受调节的磷酸酶活性或无活性全酶的形成。显性阴性LCMT-1突变体可能通过抑制不受控制的磷酸酶活性来减弱细胞周期而不引起细胞死亡。我们的研究揭示了LCMT-1严格控制PP2A功能的机制，对细胞周期和存活具有重要意义。
Proper formation of protein phosphatase 2A (PP2A) holoenzymes is essential for fitness of all eukaryotic cells. Carboxyl-methylation of PP2A catalytic subunit plays a critical role in regulating holoenzyme assembly; methylation is catalyzed by PP2A-specific methyltransferase LCMT-1, an enzyme required for cell survival. We determined crystal structures of human LCMT-1 in isolation and in complex with PP2A stabilized by a cofactor-mimic. The structures show that LCMT-1 active site pocket recognizes the carboxyl-terminus of PP2A, and interestingly, PP2A active site makes extensive contacts to LCMT-1. We demonstrated that activation of PP2A active site stimulates methylation, suggesting a mechanism for efficient conversion of activated PP2A into substrate-specific holoenzymes, thus minimizing unregulated phosphatase activity or formation of inactive holoenzymes. A dominant-negative LCMT-1 mutant attenuates cell cycle without causing cell death, likely by inhibiting uncontrolled phosphatase activity. Our studies suggested mechanisms of LCMT-1 in tight control of PP2A function, important for cell cycle and survival.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Leulliot, N;Quevillon-Cheruel, S;van Tilbeurgh, H
通讯作者：
van Tilbeurgh, H
影响因子：
4.8
作者：
Lee, Jocelyn A.;Pallas, David C.
通讯作者：
Pallas, David C.
α4是PP2A磷酸酶活性的必不可少的调节剂。
影响因子：
16
作者：
Kong, Mei;Ditsworth, Dara;Lindsten, Tullia;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
4.1
作者：
Bryant, JC;Westphal, RS;Wadzinski, BE
通讯作者：
Wadzinski, BE